Project Summary The Cancer Immunotherapy Trials Network (CITN) came about from discussions at the 2007 NCI Immunotherapy Agent Workshop, in which high-priority agents were identified that showed the potential to benefit patients with cancer?but that were not yet broadly available for investigator-initiated trials (IITs). Since 2007, a sea change has occurred in the field of cancer immunotherapy, resulting from the success of anti-PD1 and anti-PD-L1. However, most of the priority agents identified in the NCI Workshop are still not broadly available for academic IITs. Since the original award in 2011, the CITN focused on testing these high-priority agents, including 5 of the top 8 ranked agents that hit targets critical for optimal immune responses. CITN trials are among the few academic IITs of these agents, and each trial has defined biologic and therapeutic principles. Two trials have led to changes in clinical practice. The abbreviated Specific Aims for the CITN are as follows: Aim 1: (a) to continue to conduct innovative early phase multicenter immunotherapy trials for adult cancers using high-priority immunomodulatory agents; (b) to form a Pediatric CITN (PedCITN) to conduct innovative early phase multicenter immunotherapy trials for pediatric cancers using high-priority immunomodulatory agents; (c) to provide leadership, infrastructure, and statistical support for the conduct of these clinical trials; (d) to continue to access high-priority agents central to immune responses and not broadly available for IITs Aim 2: to coordinate studies with Cancer Immune Monitoring and Analysis Center (CIMAC) and other labs for specimen analysis (immune monitoring, biomarker credentialing) of adult and pediatric patients on CITN trials Scientific Goals of the CITN 1. Continue trials with T cell and natural killer cell activator and growth factor IL-15, homeostatic T cell growth factor IL-7, dendritic cell activator anti-CD40, dendritic cell growth factor Flt3L, and IDO inhibitor anti-PD1 2. Continue trials with anti-PD1 for orphan and ultra-orphan indications, including pediatric cancers 3. Conduct biopsy-intense trials to identify actionable causes of anti-PD1 failure and linked to therapeutic administration of potential rescue agents 4. Conduct trials to assess therapies that eliminate or activate the myeloid, monocytes/macrophage, and/or myeloid-derived suppressor cells that reside within most cancers 5. Conduct multicenter Phase I and early Phase II immunotherapy trials for pediatric patients with cancer The results will inform future trial designs and improve the understanding of these high-priority agents. CITN trials are designed to identify paths to regulatory approval and will likely change standard practice or spur confirmatory pivotal trials by NCI cooperative groups and industry for adult and pediatric cancers.